This project is a comprehensive study of the pulmonary circulation, its resistance vessels and its smooth muscle (PVSM) during normal vasoconstrictive and proliferative states. We will study the PVSM receptor systems (alpha-beta, H-1, H-2, etc.) by their responses to endogenous-exogenous agonists and antagonists in the perfused feline lobe under control, hypoxic and chronic proliferative conditions, by analysis of humoral and cyclic nucleotide levels of these vessels in this lobe and across the pulmonary circulation of man during cardiac catheterization, and by quantitative dose-response relations of agonist-antagonists in isolated PVSM under similar vasoactive and proliferative states. Action of neurotransmitter and vasoactive agents on excitation-contraction coupling, "resting" stiffness and relaxation will be studied in isolated resistance PVSM by intracellular microelectrodes, double sucrose gap and mechanical recording. Cyclic nucleotide, calcium-sodium effects will be analyzed in mechanical preparations of glycerinated and "skinned" PVSM. Ultrastructure of normal and proliferative resistance PVSM (both in-situ and from the special mechanomuscular preparations) will be quantitatively compared using: 1) stereologic technics for volumetric assessment of contractile elements, reticulum, subplasma-level cisterna and plasmalemma filamental attachment plaques by transmission EM; relative contributions of filaments of different morphology, sizes and number of intramyocyte and other contacts and identity of neural contacts will be assessed: 2) freeze-fracture replicas for detailed studies of PVSM plasma membrane; and 3) transmission of replicas to assess size, type and number of intracellular junctions, and number, size and distribution of intramembranous particles and of pinocytotic and filamented attachment regions.